We have examined the effects of sulfasalazine and its metabolites sulfapyridine and 5-aminosalicylic acid on antibody secretion by normal peripheral blood and intestinal mononuclear cells. Sulfasalazine and 5-aminosalicylic acid both inhibited pokeweed mitogen-stimulated secretion of immunoglobulins (Igs) A, G, and M by peripheral blood mononuclear cells in a dose-dependent manner, whereas sulfapyridine had little effect. Sulfasalazine and 5-aminosalicylic acid also inhibited spontaneous secretion of IgA by intestinal mononuclear cells, but sulfapyridine did not. Sulfasalazine inhibited pokeweed mitogen-stimulated lymphocyte proliferation, while 5-aminosalicylic acid and sulfapyridine exhibited minimal inhibition. Sulfasalazine was toxic for peripheral blood mononuclear cells, whereas 5-aminosalicylic acid and sulfapyridine were not toxic. Thus, the inhibition of antibody secretion by sulfasalazine was due to direct toxicity. On the other hand, 5-aminosalicylic acid, the therapeutically active component of sulfasalazine, was neither toxic nor antiproliferative, and appeared to exert its effects on metabolic pathways directly related to antibody synthesis. The calculated ID50 values of 5-aminosalicylic acid for antibody secretion were 1.35 mM for IgA and 1.05 mM for IgG, concentrations that are achieved in the colons of treated individuals. Indomethacin did not inhibit antibody secretion at pharmacologically relevant concentrations. 5-Aminosalicylic acid mediated inhibition of antibody secretion may play a role in inflammatory bowel disease by stopping antibody-mediated memory events involved in the induction or perpetuation of the disease process.